Melt-extruded orally administrable opioid formulations

ABSTRACT

Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.

This application is a continuation of U.S. patent application Ser. No.09/360,056, filed Jul. 23, 1999, U.S. Pat. No. 6,261,599 which is acontinuation of U.S. patent application Ser. No. 08/833,948, filed Apr.10, 1997, now U.S. Pat. No. 5,958,452, which is a continuation-in-partof PCT/US95/14745, filed Nov. 3, 1995, which is a continuation-in-partof U.S. patent application Ser. No. 08/334,209, filed Nov. 4, 1994, nowU.S. Pat. No. 5,965,161, the disclosures of which are all herebyincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to the use of melt extrusion technology inthe production of bioavailable sustained-release matrix pharmaceuticalformulations. Previously, melt extrusion has been used in the productionof immediate release formulations.

It is known in the pharmaceutical art to prepare compositions whichprovide for controlled release of pharmacologically active substancescontained in the compositions after oral administration to humans andanimals. Such slow release compositions are used to delay absorption ofa medicament until it has reached certain portions of the alimentarytract. Such sustained-release of a medicament in the alimentary tractfurther maintains a desired concentration of said medicament in theblood stream for a longer duration than would occur if conventionalrapid release dosage forms are administered.

Different methods of preparing controlled release pharmaceutical dosageforms have been suggested. For example, direct compression techniques,wet granulation techniques, encapsulation techniques and the like havebeen proposed to deliver pharmaceutically active ingredients to thealimentary tract over extended periods.

Additionally, various types of sustained release formulations are knownin the art, including specially coated pellets, coated tablets andcapsules wherein the slow release of the active medicament is broughtabout through selective breakdown of the coating of the preparation orthrough compounding with a special matrix to affect the release of adrug. Some sustained release formulations provide for related sequentialrelease of a single dose of an active compound at predetermined periodsafter administration.

It is the intent of all sustained-release preparations to provide alonger period of pharmacologic response after the administration of thedrug and is ordinarily experienced after the administration of the rapidrelease dosage forms. Such longer periods of response provide for manyinherent therapeutic benefits that are not achieved with correspondingshort acting, immediate release preparations. This is especially true inthe treatment of cancer patients or other patients in need of treatmentfor the alleviation of moderate to severe pain, where blood levels of anopioid analgesic medicament must be maintained at a therapeuticallyeffective level to provide pain relief. Unless conventional rapid actingdrug therapy is carefully administered at frequent intervals to maintaineffective steady state blood levels of the drug, peaks and valleys inthe blood level of the active drug occur because of the rapidabsorption, systemic excretion of the compound and through metabolicinactivation, thereby producing special problems in maintenance ofanalgesic efficacy.

The prior art teaching of the preparation and use of compositionsproviding the sustained-release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiological fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailablity.

In order to be absorbed, the active drug substance must be in solution.The time required for a given proportion of an active substance from aunit dosage form is determined as the proportion of the amount of activedrug substance release from a unit dosage form over a specified timebase by a test method conducted under standardized conditions. Thephysiological fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art recognizesmany satisfactory test procedures to measure dissolution time forpharmaceutical compositions, and these test procedures are described inofficial compendia world wide.

Although there are many diverse factors which influence the dissolutionof drug substance from its carrier, the dissolution time determined fora pharmacologically active substance form the specific composition isrelatively constant and reproducible. Among the different factorsaffecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified in itssteady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologicalconditions, the saturation level of the dissolved materials isreplenished form the dosage form reserve to maintain a relativelyuniform and constant dissolution concentration in the solvent mediumproviding for a steady state absorption.

The transport across a tissue absorption site of the gastrointestinaltract is influenced by the Donnan osmotic equilibrium forces on bothsides of the membrane since the direction of the driving force is thedifference between the concentrations of active substance on either sideof the membrane, i.e., the amount dissolved in the gastrointestinalfluids and the amount present in the blood. Since the blood levels areconstantly being modified by dilution, circulatory changes, tissuestorage, metabolic conversion and systemic excretion, the flow of activematerials is directed from the gastrointestinal tract into the bloodstream.

Notwithstanding the diverse factors influencing both dissolution andabsorption of a drug substance, a strong correlation has beenestablished between the in-vitro dissolution time determined for adosage form and (in-vivo) bioavailablity. The dissolution time and thebioavailablity determined for a composition are two of the mostsignificant fundamental characteristics for consideration whenevaluating sustained-release compositions.

Metal granulations techniques have also been suggested to providecontrolled release formulations. Generally, melt granulation involvesmechanically working an active ingredient in particulate form with oneor more suitable binders and/or pharmaceutically acceptable excipientsin a mixer until one or more of the binders melts and adheres to thesurface of the particulate, eventually building up granules.

U.S. Pat. No. 4,957,681 (Klimesch, et. al.) discloses a continuousprocess for preparing pharmaceutical mixtures having at least twocomponents which are continuously metered. The process includescontinuously metering the individual components of the pharmaceuticalmixture at a rate of at least 50 g/h on electronic differential meteringbalances having a metering accuracy of at least ±5% within timeintervals of less than one minute and, additionally, having screwconveyors, thereby obtaining a substantially uniformly metered mixture;and shaping the mixture. Example 1 of the '681 patent is representativeof the process. The requisite amounts of a copolymer having a K value of30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcoholand theophylline are metered via three metering balances into the hopperof an extruder and extruded. The temperatures of the extruder cylinderconsisting of six shots ranged form 30-60° C. and the die is heated to100° C. The resultant extrudate is then pressed into tablets of therequired shape. The '681 patent does not disclose preparation ofsustained release opioid pharmaceutical formulations.

N. Follonier., et al., Hot-Melt Extruded Pellets for the SustainedRelease of Highly Dosed Freely Soluble Drugs, Proceed. Intern. Symp.Control. Rel. Bioact. Mater., 18 (1991) described certain diltiazemhydrochloride formulations prepared using hot-melt screw-extrusion toobtain sustained-release pellets to be filled into hard gelatincapsules. The polymers used were ethylcellulose, a copolymer of ethylacrylate and methyl methacrylate containing quaternary ammonium groups,cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and acopolymer of ethylene and vinyl acetate. In order to lower the extrusiontemperature, some plasticizers were used.

WO 93/07859 describes drug loaded pellets produced through meltspheronization wherein the therapeutically active agent is blended withvarious excipients and binders; the formulation is fed to an extruderwhere it is heated and extruded at a speed of about 0.05 to 10 mm/sec.at approximately 60-180° C. The extrudate is then cut into pieces in apelletizer and subsequently fed to a spheronizer for uniform pelletformulation.

Despite the foregoing advances and the various techniques for preparingsustained release formulations available in the pharmaceutical art,there is a need in the art for an orally administrable opioidformulation which would provide an extended duration of effect which isalso easy to prepare, e.g via melt-granulation techniques.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to providesustained-release pharmaceutical formulations suitable for oraladministration and methods for preparing the same utilizingmelt-extrusion techniques.

It is also an object of the present invention to provide improvedmethods for producing pharmaceutical extrudates containing opioidanalgesics and pharmaceutical acceptable hydrophobic materials via meltextrusion techniques.

It is a further object of the present invention to provide asustained-release melt extruded multi-particulate formulation which neednot be spheronized in order to obtain a final dosage form.

It is also an object of the present invention to provide methods oftreatment for human patients in need of opioid analgesic therapy usingdosage forms prepared in accordance with the methods disclosed herein.

In accordance with the above objects and others which will be apparentfrom the further reading of the specification and of the appendedclaims, the present invention is related in part to the surprisingdiscovery that sustained-release oral opioid analgesic formulations maybe prepared utilizing melt extrusion techniques to provide bioavailableunit dose products which provide analgesic in a patient for, e.g., 8-24hours.

The invention is also related in part to a new melt-extruded oralsustained-release dosage forms which comprise a pharmaceuticallyacceptable hydrophobic material, a retardant selected from waxes, fattyalcohols, and fatty acids, and a drug.

More particularly, one aspect of the present invention is related to apharmaceutical extrudate including an opioid analgesic dispersed in amatrix. Preferably, the extrudate is strand or spaghetti-shaped and hasdiameter from about 0.1 to about 5 mm. The extrudate is divided intounit doses of the opioid analgesic for oral administration to a patient,and provides a sustained analgesic effect for 8-24 hours or more.

The matrices preferably include a hydrophobic material and a secondretardant material (preferably a hydrophobic fusible carrier) which actsto further slow or control the release of the therapeutically activeagent which the formulation is exposed to aqueous solution in-vitro, orexposed to gastic and/or intestinal fluids.

Preferably, the hydrophobic material is selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil or hydrogenatedvegetable oil, or mixtures thereof.

The retardant material (hydrophobic fusible carrier) is preferablyselected from natural and synthetic waves, fatty acids, fatty alcoholsand mixtures of the same. Examples include beeswax and carnauba wax,stearic acid, and stearyl alcohol. This list is of course not meant tobe exclusive.

The extrudate may be cut into multiparticulates by any cutting meansknown in the art. Preferably, the multiparticulates have a length offrom about 0.1 to 5 mm in length. The multiparticulates may then bedivided into unit doses such that each individual unit dose includes adose of opioid analgesic sufficient to provide analgesia to a mammal,preferably a human patient.

The unit doses of multiparticulates may then be incorporated into asolid pharmaceutical dosage formulation, e.g. via compression or shapinginto tablets, by placing a requisite amount inside a gelatin capsule, orby forming the extruded product into the form of a suppository.

The pharmaceutical extrudates of the present invention may be preparedby blending the drug together with all matrix ingredients (hydrophobicmaterial, binder and any additional (optional) excipients), feeding theresultant mixture into an extruder heated to the requisite temperaturenecessary to soften the mixture sufficiently to render the mixtureextrudable; extruding the viscous, heated mass as a spaghetti-likestrand; allowing the extrudate to congeal and harden, and then dividingthe strand into desired pieces. This may be accomplished, e.g., bycutting the strands into pellets of 1.5 mm in diameter and 1.5 mm inlength. Preferably, the extrudate has a diameter of from about 0.1 and 5mm and provides sustained release of said opioid analgesic for a timeperiod of from about 8 to about 24 hours.

Another aspect of the invention is directed to pharmaceutical dosageforms including the extrudate prepared as outlined above. The extrudateis cut into multiparticulates using any cutting means known in the art,e.g a blade. The multiparticulates are then divided into unit dosescontaining an effective amount of opioid analgesic to provide analgesiaor pain relief in a human patient over the desired. dosing interval. Theunit dose of multiparticulates may then be incorporated into tablets,e.g. via direct compression, formed into suppositories, or encapsulatedby any means known in the art.

In yet a further aspect of the invention, there is provided a method oftreating a patient with sustained-release formulations prepared asdescribed above. This method includes administering a dosage formcontaining the novel extrudate to a patient in need of opioid analgesictherapy. For purposes of the present invention, a unit dose isunderstood to contain an effective amount of the therapeutically activeagent to produce pain relief and/or analgesia to the patient. Oneskilled in the art will recognize that the dose of opioid analgesicadministered to a patient will vary due to numerous factors; e.g. thespecific opioid analgesic(s) being administered, the weight andtolerance of the patient, other therapeutic agents concomitantly beingadministered, etc.

As mentioned above, in order for a dosage form to be effective for itsintended purpose, the dosage form must be bioavailable. For purposes ofthe present invention, the term “bioavailable” is defined as the totalamount of a drug substance that is absorbed and available to provide thedesired therapeutic effect after administration of a unit dosage form.Generally, the bioavailablity of a given dosage form is determined bycomparison to a known reference drug product, as commonly determined andaccepted by Governmental Regulatory Agencies, such as the United StatesFDA.

The term “bioavailabity” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage form and is available at the side of drugaction.

The terms “sustained release”, “extended duration”, and “controlledrelease” are defined for purposes of the present invention as therelease of the drug (e.g., opioid analgesic) at such a rate that blood(e.g., plasma) levels are maintained within the therapeutic range butbelow toxic levels over a period of time greater than 8 hours, morepreferably for about 12 to about 24 hours, or longer.

The term “unit dose” is defined for purposes of the present invention asthe total amount of multiparticulates needed to administered a desireddose of therapeutically active agent (e.g., opioid analgesic) to apatient.

The extrudates of the present invention preferably permit release of theopioid (or salts thereof) over a sustained period of time in an aqueousmedium. The term “aqueous medium” is defined for purposes of the presentinvention as any water-containing medium, e.g. water, pharmaceuticallyacceptable dissolution medium, gastric fluid and/or intestinal fluid andthe like.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawing is illustrative of an embodiment of the inventionand is not means to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graph displaying the dissolution results of Examples 1 and2;

FIG. 2 is a graph displaying the dissolution rates of Example 3-6;

FIGS. 3 and 4 are graphs displaying the pH dependency of the dissolutionresults of Examples 3 and 6 respectively;

FIG. 5 is a graph displaying the dissolution results of Examples 7 and 8vs. Example 6;

FIG. 6 is a graph displaying the dissolution results of Examples 9 and10;

FIG. 7 is a graph displaying the dissolution results of Examples 11 and12;

FIG. 8 is a graph displaying the dissolution results of Examples 15 and16;

FIG. 9 is a schematic representation of a system for carrying out thepresent invention;

FIG. 10 is a graph displaying the fed/fast bioavailablity results forExample 20;

FIG. 11 is a graph displaying the plasma morphine concentrations ofExample 21 obtained form administration of the capsules from Example 6vs. MS Conti®;

FIG. 12 is a graph displaying the plasma oxycodone concentrations ofExample 22 obtained from administrating the capsules from Example 11 and13 vs. OxyContin®;

FIG. 13 is a graphical representation of the plasma oxycodoneconcentrations of Example 14;

FIG. 14 is a graphical representation of the hydromorphoneconcentrations of Example 24 using the capsules from example 17 vs.Dilaudid®;

FIG. 15 is a graph displaying the plasma hydromorphone concentrations ofExample 24 using the capsules of Example 18 vs. Dilaudid®;

FIG. 16 is a graph of the steady-state plasma hydromorphoneconcentrations of Example 25 using the capsules of Example 17; and

FIG. 17 is a graph of the plasma hydromorphone concentrations of Example26 using the capsules of Example 19,

DETAILED DESCRIPTION

In one aspect of the invention, the sustained-release dosage formscomprise an opioid analgesic as the therapeutically active agent. Insuch formulations, the drug is incorporated into a melt-extruded strandwhich includes a pharmaceutically acceptable hydrophobic material suchas an alkylcellulose or an acrylic polymer or copolymer. In certainembodiments, it is preferably to further add to the blend a plasticizersfor the hydrophobic material in order to reduce the extrusiontemperature. The choice of the most suitable plasticizer is made basedon its ability to lower the glass transition temperature (Tg) of thepolymer. In preferred alternative embodiments, a hydrophobic fusiblecarrier (which may also act as a binder) is utilized instead of aplasticizer. The hydrophobic fusible carrier preferably imparts a slowerrelease of the therapeutically active agent form the melt extrudedformulation. Any further pharmaceutical excipients known to thoseskilled in the art may be added as deemed necessary.

Another aspect of the invention is directed to improved melt extrudedmatrices which comprise a hydrophobic material and a fatty binder suchas previously specified. In accordance therewith, a therapeuticallyactive agent is combined with one or more suitable hydrophobic materialsand a hydrophobic fusible carrier is extruded to form an extrudate. Theextrudate may then be cut into multiparticulates which are subsequentlyincorporated into sustained release dosage forms.

Therapeutically Active Agents

Therapeutically active agents which may be used in accordance with thepresent invention include both water soluble and water insoluble drugs.Examples of such therapeutically active agents include antihistamines(e.g., dimenhydrinate, diphenhydramine, chlorpheniramine anddexchlorpheniramine maleate), analgesics (e.g., aspirin, codeine,morphine, dihydromorphone, oxycodone, et.), non-steroidalanti-inflammatory agents (e.g., naproxen, dichlofenae, indomethacin,ibuprofen, sulindac), anti-emetics (e.g., meloclopramide,methylnaltrexone), anti-epileptics (e.g., phentoin, meprobamate andnitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem andnicardipine), anti-tussive agents and expectorants (e.g., codeinephosphate), anti-asthmatics (e.g. theophylline), antacids,anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g.,insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide),anti-hypotensives (e.g., propranolol, clonidine), antihypertensives(e.g, clonidine, methyldopa), bronchodilators (e.g., albuterol),steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics(e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics,antidiarrheals, mucolytics, sedatives, decongestants, laxatives,vitamins, stimulants (including appetite suppressants such asphenylpropanolamine), as well as salts, hydrates, and solvents of thesame.

In embodiments of the invention directed to opioid analgesics, theopioid analgestics used in accordance with the present invention includealfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromophone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, phopheptazine, promedol, properidine, propiram,propozyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like. The opioid analgesic may be in the form ofthe free base, or in the form of a pharmaceutically acceptable salt, orin the form of a pharmaceutically acceptable complex.

In certain preferred embodiments, the opioid analgesic is selected frommorphine, codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, oxymorphone, tramadol or mixturesthereof.

In one preferred embodiment the sustained-release opioid oral dosageform of the present invention includes hydromorphone as thetherapeutically active ingredient in an amount from about 4 to about 64mg hydromophone hydrochloride. Alternatively, the dosage form maycontain molar equivalent amounts of other hydromorphone slats or of thehydromorphone base. In other preferred embodiments where the opioidanalgesic is other than hydromophone, the dosage form contains anappropriate amount to provide a substantially equivalent therapeuticeffect. For example, when the opioid analgesic comprises morphine, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 800 mg morphine, by weight (based on morphinesulfate). When the opioid analgesic comprises oxycodone, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 400 mg oxycodone. When the opioid analgesic istramadol, the sustained-release oral dosage forms of the inventioninclude from about 50 mg to about 800 mg tramadol by weight, based onthe hydrochloride salt.

The sustained-release dosage forms of the present invention generallyachieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction.

In the present invention, the oral opioid analgesics have beenformulated to provide for an increased duration of analgesic.Surprisingly, these formulations, at comparable daily dosages ofconventional immediate-release drug, are associated with a lowerincidence in severity of adverse drug reactions and can also beadministered at a lower daily dose than conventional oral medicationwhile maintaining pain control.

When the therapeutically active agent included in the dosage forms ofthe present invention is an opioid analgesic, the dosage form mayfurther include one or more additional which may or may not actsynergistically with the opioid analgesics of the present invention.Examples of such additional therapeutically active agents includenon-steroidal anti-inflammatory agents, including ibuprofen, diclofenac,naproxen, benoxaprofen, flubriprofen, fenoprofen, flubufen, ketoprofen,idoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acematacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like.Other suitable additional drugs which may be included in the dosageforms of the present invention include acetaminophen, aspirin,salicylate-derived analgesics and antipyretics or salts thereof, andother non-opioid analgesics.

The additional (non-opioid) therapeutically active agent may be includedin control release form or in immediate release form. The additionaldrug may be incorporated into the controlled release matrix along withthe opioid; incorporated as a separated controlled release layer orimmediate release layer; or may be incorporated as a powder,granulation, etc., in a gelatin capsule with the extrudates of thepresent invention.

Matrix Ingredients

The extrudates of the present invention include at lease one hydrophobicmaterial. The hydrophobic material will preferably impart sustainedrelease of the opioid analgesic to the final formulation. Preferredhydrophobic materials which may be used in accordance with the presentinvention include alkylcelluloses such as natural or syntheticcelluloses derivative (e.g. ethylcellulose), acrylic and methacrylicacid polymers and copolymers, shellac, zein, was-type substancesincluding hydrogenated castor oil or hydrogenated vegetable oil, ormixtures thereof. This list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material which is capable ofimparting sustained release of the active agent and which melts (orsoftens to the extent necessary to be extruded) may be used inaccordance with the present invention.

In certain preferred embodiments of the present invention, thehydrophobic material is a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid an methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxyethyl methacryaltes, cynaoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methancrylate copolymers.In other embodiments, the hydrophobic material is selected frommaterials such as hydroxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing.

The retardant material is preferably a hydrophobic fusible carrier whichmay comprise one or more water-insoluble wax-like thermoplasticsubstances possibly mixed with one or more wax-like thermoplasticsubstances being less hydrophobic than said one or more water-insolublewas-like substances. In order to achieve constant release, theindividual was-like substances in the binder material should besubstantially non-degradable and insoluble in gastrointestinal fluidsduring the initial release phases.

Useful water-insoluble wax-like substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

Such hydrophobic fusible carrier materials are preferablywater-insoluble with more or less pronounced hydrophilic and/orhydrophobic trends. Preferably, the retardant materials useful in theinvention have a melting point from about 30 to about 200° C.,preferably from about 45 to about 90° C. Specifically, the hydrophobicfusible carrier may comprise natural or synthetic waxes, fatty alcohols(such as lauryl, myristyl stearyl, cetyl or preferably cetostearylalcool), fatty acids, including but not limited to fatty acid esters,fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenatedfats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol andhydrophobic and hydrophilic polymers having hydrocarbon backbones.Suitable waxes include, for example, beeswax, glycowax, castor was andcarnauba wax. For purposes of the present invention, a wax-likesubstance is defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to about 100° C.

Suitable hydrophobic fusible carrier materials which may be used inaccordance with the present invention include digestible, lone chain(C₈-C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons,such as fatty acids, fatty alcohols, glyceryl esters of fatty acids,mineral and vegetable oils and natural and synthetic waxes. Hydrocarbonshaving a melting point of between 25° and 90° are preferred. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

In addition to the above ingredients, a sustained-release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a sustained-release matrix incorporating melt-extruded multiparticulatesmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. Specific examplesof pharmaceutically acceptable carriers and excipients that may be usedto formulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986),incorporated by reference herein.

In order to facilitate the preparation of a solid, sustained-releaseoral dosage form according to this invention there is provided, in afurther aspect of the present invention, a process for the preparationof a solid, sustained-release oral dosage form according to the presentinvention comprising incorporating opioids or a salt thereof in asustained-release melt-extruded matrix. Incorporation in the matrix maybe effected, for example, blending the opioid analgesic, together withat least one hydrophobic material and preferably the additionalretardant material (hydrophobic fusible carrier) to obtain a homogeneousmixture. The homogeneous mixture is then heated to a temperaturesufficient to at least soften the mixture sufficiently to extrude thesame. The resulting homogeneous mixture is then extruded, e.g., using atwin-screw extruder, to form strands. The extrudate is preferably cooledand cut into multiparticulates by any means known in the art. Thestrands are cooled and cut into multiparticulates. The multiparticulatesare then divided into unit doses. The extrudate preferably has adiameter of from about 0.1 to about 5 mm and provides sustained releaseof the therapeutically active agent for a time period of from about 8 toabout 24 hours.

An optional process for preparing the melt extrusion, multiparticulatesand unit doses of the present invention includes directly metering intoan extruder a water-insoluble retardant, a therapeutically active agent,and an optional binder; heating said homogeneous mixture; extruding saidhomogeneous mixture to thereby form strands; cooling said strandscontaining said homogeneous mixture; and cutting said strands intoparticles having a size form about 0.1 mm to about 12 mm; and dividingsaid particles into unit doses. In this aspect of the invention, arelatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a retardant as described herein. In this regard, themelt-extruded multiparticulates will be of a range of from about 0.1 toabout 12 mm in length and have a diameter of from about 0.1 to about 5mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size rangesuch as beads, microspheres, seeds, pellets, etc.

A particular advantage provided by the invention is the preparation ofsustained-release melt-extruded multiparticulate formulations which donot require further processing, e.g., the extrudate may simply be cutinto desired lengths and divided into unit doses of the therapeuticallyactive agent without the need of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained-release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above and hereby incorporated byreference.

In yet a further embodiment, the extrudate can be shaped intosuppositories containing a unit dose of the therapeutically activeagent. This may be accomplished using techniques and equipment wellknown to those skilled in the art.

Optionally, the sustained-release melt-extruded multiparticulate systemor tablets can be coated, or the gelatin capsule can be further coated,with a sustained-release coating comprising one of the hydrophobicmaterials described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level form about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compoundutilized and the desired release rate, among other things. In certainpreferred embodiments of the present invention, the hydrophobic polymercomprising the sustained-release coating is a pharmaceuticallyacceptable acrylic polymer, such as those described herein above. Thesolvent which is sued for the hydrophobic material in the coating may beany pharmaceutically acceptable solvent, including water, methanol,ethanol, methylene chloride and mixtures thereof.

The unit dosage forms of the present invention may further includecombinations of melt-extruded multiparticulates containing one or moreof the therapeutically active agents disclosed above before beingencapsulated. Furthermore, the unit dosage forms can also include anamount of an immediate release therapeutically active agent for prompttherapeutic effect. The immediate release therapeutically active agentmay be incorporated, e.g., as separate pellets within a gelatin capsule,or may be coated on the surface of the compressed table which has beenprepared from the multiparticulate extrudate as set forth above.

The controlled-release formulations of the present invention slowlyrelease the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic polymer, by varying the amount ofplasticizer relative to hydrophobic polymer, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc. In certain embodiments of the invention, the thesustained-release dosage forms of the present invention preferablyrelease the therapeutically active agent at a rate that is independentof pH, e.g., between pH 1.6 and 7.2. In other embodiments, theformulations can be designed to provide a pH-dependent release of thetherapeutically active agent.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tabletted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

Opioid Analgesic Formulations

In certain preferred embodiments, the invention is directed tosustained-release oral opioid formulations which are administrable on aonce-a-day basis, and which are prepared from the melt extrudatesdescribed herein. Such dosage forms will provide and in-vitro release(when assessed by the USP Paddle or Basket Method at 100 prm at 900 mlaqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 1 to about42.5% opioid released after one hour, from about 5 to about 65% opioidreleased after 2 hours, from about 15 to about 85% opioid released after4 hours, from about 20 to about 90% opioid released after 6 hours, fromabout 35 to about 95% opioid released after 12 hours, from about 45 toabout 100% opioid released after 18 hours, and from about 55 to about100% opioid released after 24 hours, by weight. Such formulations mayfurther be characterized by a peak plasma level at form about 2 to about8 hours after oral administration, and preferably from about 4 to about6 hours after administration. Such formulations are furthercharacterized by a W₅₀ from about 4 to about 12 hours.

In certain preferred embodiments, the oral 24 hour sustained-releaseopioid dosage form provides a rapid rate of initial rinse in the plasmaconcentration of the opioid after oral administration, such that thepeak plasma level obtained in-vivo occurs from about 2 to about 8 hoursafter oral administration, and/or the absorption half-life is from about1 to about 8 hours after oral administration (in the fasted state). Morepreferably in this embodiment the absorption half-life is 1-6 hours andpossibly 1-3 hours after oral administration (in the fasted state). Suchformulations provide an in-vitro dissolution under the conditionsspecified above, from about 12.5 to about 42.5% opioid released afterone hour, from about 25 to about 65% opioid released after 2 hours, fromabout 45 to about 85% opioid released after 4 hours, and greater thanabout 60% opioid released after 8 hours, by weight.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

MELT-EXTRUSION TECHNIQUES

Typical melt extrusion systems capable of carrying-out the presentinvention include a suitable extruder drive motor having variable speedand constant torque control, start-stop controls, and ammeter. Inaddition, the system will include a temperature control console whichincludes temperature sensors, cooling means and temperature indicatorsthroughout the length of the extruder. In addition, the system willinclude an extruder such as twin-screw extruder which consists of twocounter-rotating intermeshing screws enclosed within a cylinder orbarrel having an aperture or die at the exit thereof. The feed materialsenter through a feed hopper and is moved through the barrel by thescrews and is forced through the die into strands which are thereafterconveyed such as by a continuous movable belt to allow for cooling andbeing directed to a pelletizer or other suitable device to render theextruded ropes into the multiparticulate system. The pelletizer canconsist of rollers, fixed knife, rotating cutter and the like. Suitableinstruments and systems are available from distributors such as C. W.Brabender Instruments, Inc. of South Hackensack, N.J. Other suitableapparatus will be apparent of those of ordinary skill in the art.

A further aspect of the invention is related to the preparation of meltextruded multiparticulates as set forth above in a manner which controlsthe amount of air included in the extruded product. By controlling theamount of air included in the extrudate, it has been surprisingly foundthat the release rat of the therapeutically active agent from the, e.g.,multiparticulate extrudate, can be altered significantly. In certainembodiments, it has been surprisingly found that the pH dependency ofthe extruded product can be altered as well.

A further aspect of the invention is related to the preparation of meltextruded multiparticulates as set forth above in a manner which controlsthe amount of air included in the extruded product. By controlling theamount of air included in the extrudate, it has been surprisingly foundthat the release rate of the therapeutically active agent form the,e.g., multiparticulate extrudate, can be altered significantly. Incertain embodiments, it has been surprisingly found that the pHdependency of the extruded product can be altered as well.

Thus, in a further aspect of the invention, the melt extruded product isprepared in a manner which substantially excludes air during theextrusion phase of the process. This may be accomplished, for example,by using a Leistritz extruder having a vacuum attachment. It has beensurprisingly found that extruded multiparticulates prepared according tothe invention using the Leistritz extruder under vacuum provides amelt-extruded product having different physical characteristics. Inparticular, the extrudate is substantially non-porous when magnified,e.g., using a scanning electron microscope which provides an SEM(scanning electron micrograph). Contrary to conventional thought, it hasbeen found that such substantially non-porous formulations provide afaster release of the therapeutically active agent, relative to the sameformulation prepared without vacuum. SEMs of the multiparticulatesprepared using an extruder under vacuum appear very smooth, and themultiparticulates tend to be more robust than those multiparticulatesprepared without vacuum. It has been observed that in at least certainformulations, the use of extrusion under vacuum provides an extrudedmultiparticulate product which is more pH-dependent than its counterpartformulation prepared without vacuum.

GENERAL PELLET MANUFACTURING PROCEDURE

The following technique was used to manufacture the extrudate andmultiparticulates for Examples 1-26.

Blend the required amount of drug, hydrophobic material and binder alongwith any additional excipients.

Charge a powder feeder with proper amount of drug/excipients blend.

Set temperatures of extruder heating zones to the required temperature,depending on the formulation. Typically, the temperature should be setat about 83° C. Wait until the corresponding heat zones reach steadytemperatures. Set the extruder screw rotation speed to 20 rpm. Start thefeeder, the conveyor and the pelletizer. After the excipients are meltedand the drug is embedded in the molten mixture, the resultant viscousmass is extruded as spaghetti-like strands. The diameter of the extruderaperture can be adjusted to vary the thickness of the resulting strand.

Set the conveyor belt speed to an appropriate speed (e.g., 3-100ft/min). Allow the extruded semisolid strand(s) to be congealed and/orhardened while transported to the pelletizer on the conveyor belt.Additional cooling devices may be needed to ensure proper congealing.(The conveyor belt may not be needed to cool the strand, if the materialconceals rapidly enough.)

Set the roller knife to an appropriate speed (e.g., to 3-100 ft/min and100-800 rpm). Cut the congealed strands to desired size (e.g., 3-5 mm indiameter, 0.3-5 mm in length).

Collect the pellet product.

Fill a desired weight of pellets into hard gelatin capsules to obtain anappropriate doses of the drug.

DISSOLUTION METHOD

The following dissolution method was used to obtain dissolution profilesfor the dosage forms of Example 1-25:

(USP 11 Paddle at 100 rpm at 37° C.)

Media—1st hour in 700 ml simulated gastric fluid (SGF), pH 1.2 withoutenzyme thereafter, 900 ml simulated intestinal fluid (SIF), pH 7.5without enzyme

Using HPLC procedures for assay

The following examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Controlled Release Chlorpheniramine Formulations

In these examples, chlorpheniramine maleate controlled release pelletswere prepared according to the above manufacturing procedure usingethylcellulose and an acrylic polymer (Eudragit RSPO), respectively asthe retardant. The formulations are set forth in Tables 1 and 2 below.The dissolution of these formulations is set forth in FIG. 1. Drugrelease rate form ethylcellulose pellets (prepared at 105° C.) issignificantly slower than that from Eudragit RSPO pellets (prepared at85° C.).

TABLE 1 EX. 1 Composition Amt. (mg) per Capsule Chlorpheniramine Maleate60 Ethyl Cellulose 84 Stearic Acid 36 Total 180

TABLE 2 EX. 2 Composition Amt. (mg) per Capsule Chlorpheniramine Maleate60 Eudragit RSPO 84 Stearic Acid 36 Total 180

EXAMPLES 3-6 Controlled Release Morphine Formulations

Ex.3 The excipients used in Ex. 2 were employed to make morphine sulfatecontrolled release pellets.

TABLE 3 EX. 3 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 42 Stearic Acid 18 Total 120

The drug release rate of Example 3 was slower than expected especiallyduring later hours of the dissolution.

Ex. 4-5 Examples 4-5 were prepared in accordance with Example 3 above.To increase the drug dissolution rate during later hours, varyingamounts of Eudragit L-100 were incorporated in the formulation. The drugdissolution rate increases with increasing amount of Eudragit L-100 inthe formulation. The morphine sulfate capsule formulation are set forthin tables 4-6 below:

TABLE 4 EX. 4 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 38.4 Eudragit L-100 3.6 Stearic Acid 18 Total 120

TABLE 5 EX. 5 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 18 Total 120

Ex. 6. A sustained release morphine sulfate formulation was preparedhaving the ingredients listed in Table 6 below:

TABLE 6 Percentage Ingredients Amt(mg)/Capsule in Formula MorphineSulfate 60 50 Eudragit RSPO 36 30 Eudragit L-100 6 5 Stearic Acid 18 15Total 120 100

The formulation of Example 6 was prepared as follows:

Pellet Manufacture

a. Extruder system description. The twin screw extruder is consisted ofa pair of counter rotating screws and a barrel block equipped withheating/cooling zones. The extrudate is delivered to a pelletizerthrough a conveyor belt and cut into pellets of the desirable size.

b. Manufacturing procedure-

1. Blend the drug and all the excipients in a proper mixer.

2. Place the mixture in a powder feeder.

3. Set temperatures of the extruder heating zones to approximately 83°C.

4. Set the extruder screw rotation speed to 20 rpm.

5. Start the feeder, the conveyor and the pelletizer.

6. After the excipients are melted and the drug embedded in the moltenmixture, the viscous mass is extruded as spaghetti-like strands.

7. The extrudate is congealed and hardened while being delivered to thepelletizer on the conveyor belt.

8. The roller knife of the pelletizer cuts the strands into pellets of1.5 mm in diameter and 1.5 mm in length.

Encapsulation

After the pellets were manufactured, 120 mg of pellets are encapsulatedin size #2 heard gelatin capsules, rendering capsules containing 60 mgof morphine sulfate. These capsules were then tested using the followingdissolution methodology:

The capsules of Examples 6 were found to have the following dissolutionresults:

Time (hr)  1  2  4 8 12 18  24 Mean % dissolved 16 33 52 72 84 95 102

As seen in FIG. 3, the drug dissolution rate obtained from the productof Ex. 3 showed a significant pH dependency. The release rate was slowerin SIF (simulated intestinal fluid) than in SGF (simulated gastricfluid).

In FIG. 4, it can be seen that due to the addition of Eudragit L-100,the drug dissolution rate obtained from Ex. 6 was less pH dependent. Thedrug release rate was faster in SIF during later hours of dissolutionwhich is desirable for complete bioavailablity.

EXAMPLES 7-8

As demonstrated in FIG. 5, with proper choice of plasticizers, the drugrelease rate from the formula containing Eudragit L-100 can be reduced.This may be necessary to achieve desirable plasma drug concentrationprofiles after oral administration of the pellets.

TABLE 7 EX. 7 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 9 Diethyl Phthalate 9Total 120

TABLE 8 EX. 8 Composition Amt. (mg) per Capsule Morphine Sulfate 60Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 9 Tributyl Citrate 9Total 120

EXAMPLES 9-10

A different polymer/wax combination was used as a alternativeformulation. As seen in FIG. 6, the drug dissolution rate fromethylcellulose/polyvinyl acetate phthalate was somewhat faster.

TABLE 9 EX. 9 Composition Amt. (mg) per Capsule Morphine Sulfate 60Ethyl Cellulose 38.4 Polyvinyl Acetate Phthalate 3.6 Stearic Acid 18Total 120

TABLE 10 EX. 10 Composition Amt. (mg) per Capsule Morphine Sulfate 60Ethyl Cellulose 34.8 Polyvinyl Acetate Phthalate 7.2 Stearic Acid 18Total 120

EXAMPLES 11-14 Controlled Release Oxycodone Formulations

The formula used in Ex. 6 was applied to oxycodone hydrochloride. Due tothe higher potency of oxycodone, only 20 mg of drug was used. Themissing 40 mg was replaced by 40 mg of tale (Ex. 12). No replacement wasused in Ex. 11. When tested in only SGF or SIF, the use of Eudragit Lcauses the formulation to become less pH dependent. The results areshown in FIG. 7.

TABLE 11 Percentage Ingredients Amt(mg)/Capsule in Formula Oxycodone HCL20 25 Eudragit RSPO 36 45 Eudragit L-100  6 7.5 Stearic Acid 18 22.5Total 80 100

The pellet manufacturing procedure and the dissolution method are thesame as described in Example 6.

The above capsules were found to have the dissolution results set forthin Table 11a below:

TABLE 11a Time (hr)  1  2  4 8 12 18  24 Mean % dissolved 14 29 45 66 8194 101

TABLE 12 EX. 12 Composition Amt. (mg) per Capsule OxycodoneHydrochloride 20 Eudragit RSPO 36 Eudragit L-100  6 Stearic Acid 18 Talc40 Total 120 

Ex. 13 Oxycodone HCl once-a-day capsules were produced with thefollowing formula using the technology described in Example 6. Theformulation is set forth in Table 13 below.

TABLE 13 Percentage Ingredients Amt(mg)/Capsule in Formula Oxycodone HCl20 25 Eudragit RSPO 39 48.75 Eudragit L-100  3 3.75 Stearic Acid 18 22.5Total 80 100

The pellet manufacturing procedure is the same as described in Example6. However, 80 mg of pellets were encapsulated to contain 20 mg ofoxycodone HCL.

The above capsules were tested using the following dissolutionmethodology:

1. Apparatus—USP type II (paddle), 100 rpm at 37° C.

2. Media—Either 900 ml simulated gastric fluid (SGF), pH 1.2 withoutenzyme; or 900 ml simulated intestinal fluid (SIF), pH 7.5 withoutenzyme.

3. Analytical method—High performance liquid chromatography.

The dissolution results are set forth in Table 13a below:

TABLE 13a Time (hr)  1  2  4  8 12 18 24 Mean % dissolved (SGF) 13 20 2941 51 62 71 Mean % dissolved (SIF) 14 21 31 44 57 68 80

Ex. 14 To prepare an oxycodone HCl controlled release tablet which woulddissolve preferentially in a lower pH, the following formula is used:

TABLE 14 Ingredients Amt(mg)/Tablet Percentage in Formula Oxycodone HCl40 30.8 Eudragit RS30D (solid) 14 10.8 Spray Dried Lactose 35.25 27.1PVP 5 3.9 Triacetin 2 1.5 Stearyl Alcohol 25 19.2 Talc 2.5 1.9 MagnesiumStearate 1.25 0.9 Film Coat 5 3.9 Total 130 100

Total Manufacture

1. Mix Eudragit RS30D (suspension) and Triacetin for 5 minutes.

2. Place spray dried lactose, oxycodone HCl, PVP, in a fluid bed drier.

3. Spray the suspension onto the powders under fluidization.

4. Pass the granulation though a Comil to reduce lumps.

5. Melt stearyl alcohol at 70° C.

6. Incorporate the molten stearyl alcohol into the dry granulation in aCollete Mixer.

7. Transfer the waxed granulation to a cooling tray and allow thegranulation to congeal.

8. Pass the granulation through a Comil.

9. Mix the waxed granulation with tale and magnesium stearate in aCollete Mixer.

10. Compress the lubricated granulation into tablets using a rotarytablet press.

11. Film coat the tablets.

These tablets were then tested using the following dissolutionmethodology described in Example 13.

The above tablets were found to have the following dissolution results:

TABLE 14a Time (hr)  1  2  4  8 12 Mean % dissolved SGF 39 53 70 90 99Mean % dissolved SIF 35 48 65 83 93

EXAMPLES 15-19 Controlled Release Hydromorphone Formulations

Ex. 15-16 The formula used in Ex. 6 was applied to hydromorphonehydrochloride. Due to the higher potency of hydromorphone, only 8 mg ofdrug was used. The missing 52 mg was replaced by 52 mg of talc (Ex. 16)or 52 mg of excipients (Ex. 15). The results are shown in FIG. 8.

TABLE 15 EX. 15 Composition Amt. (mg) per Capsule HydromorphoneHydrochloride 8 Eudragit RSPO 67.2 Eudragit L-100 11.2 Stearic Acid 33.6Total 120

TABLE 16 EX. 16 Composition Amt. (mg) per Capsule HydromorphoneHydrochloride  8 Eudragit RSPO 36 Eudragit L-100  6 Stearic Acid 18 Talc52 Total 120 

Ex. 17 Hydromorphone HCl once-a-day capsules were produced with theformula set forth in Table 17 below using the technology described inExample 6.

TABLE 17 Percentage Ingredients Amt(mg)/Capsule in Formula HydromorphoneHCL  8 10 Eudragit RSPO 53 66.25 Stearyl Alcohol 19 23.75 Total 80 100

The pellet manufacturing procedure is the same as describe din Example6. However, pellets of 1.0 mm in diameter and 1.0 mm in length wereprepared. Each capsule holds 80 mg of pellets and contains 8 mg ofhydromorphone HCL.

The above capsules were tested using the dissolution methodologydescribed in Example 6.

The above capsules were found to have the dissolution results set forthin Table 17a below:

TABLE 17a Time (hr)  1  2  4  8 12 18 24 Mean % dissolved 17 28 32 45 5669 82

Ex. 18 Hydromophone HCl once-a-day capsules were produced with theformula set forth in Table 18 below as the second example of thetechnology described in Example 6.

TABLE 18 Percentage Ingredients Amt(mg)/Capsule in Formula HydromorphoneHCl  8  10 Eudragit RSPO 48  60 Stearyl Alcohol 24  30 Total 80 100

The pellet manufacturing procedure and the dissolution method are thesame as described in Example 6.

The above capsules were found to have the dissolution results set forthin Table 18a below:

TABLE 18a Time (hr)  1  2  4 8 12 18 24 Mean % dissolved 23 29 40 56 6984 96

Ex. 19 Hydromorphone HCl once-a-day capsules were produced with thefollowing formula according to the method described Example 6.

TABLE 19 Percentage Ingredients Amt(mg)/Capsule in Formula HydromorphoneHCL 8 10 Eudragit RSPO 41.5 51.9 Eudragit L-100 8.5 10.6 Stearic Acid 2227.5 Total 80 100

The manufacturing procedure of the pellets and the dissolution methodare the same as described in Example 6.

The above capsules were found to have the following dissolution results:

TABLE 19a Time (hr) 1  2  4  8 12 18 24 Mean % dissolved 4 14 36 52 6475 84

EXAMPLE 20

In this Example, a bioavailablity study was undertaken. Fourteensubjects were given the morphine sulfate formulations of Example 3. Theresults are provided in Table 20 below in FIG. 10.

TABLE 20 Group AUC Cmax Tmax Example 3 Fasted 230 15.7 2.1 Example 3 Fed213 14.0 3.2

From the above data, it can be seen that the formulation is an idealcandidate for an extended release or once-a-day product without a foodeffect.

EXAMPLE 21 Bioavailablity of Morphine Sulfate Melt ExtrusionMultiparticulate 60 mg Capsules

A bioavailablity study of morphine capsules of Example 6 was conductedin 12 normal male volunteers. Capsules of 60 mg in strength wereadministered either with or without food in a single dose, two-waycrossover study. Blood samples were taken periodically and assayed formorphine concentrations using gas chromatography with mass detection(G/MS). From the data, the following pharmacokinetic parameters werecalculated and are indicated in Table 21 below.

TABLE 21 AUC, Treatment n · hr/ml Cmax, n/ml Tmax, hr Fasted 228 15.72.1 Fed 210 14.0 3.2

When compared to the typical blood levels of MS Contin®, a single dosetwice-a-day marketed morphine sulfate 30 mg tablets, in the fastedstate, it can be seen that the capsules of Example 6 are suitable foronce daily administration. At the 24th hour the blood levels are wellabove MS-Contin and within the therapeutic range (FIG. 11).

EXAMPLE 22 Bioavailablity of OXY-MEM 20 mg Capsules.

A bioavailablity sturdy of oxycodone capsules of examples 11 and 13 wasconducted in 10 normal male volunteers. Capsules of example 13 wereadministered either with or without food. Capsules of example 11 wereadministered without food. The study was conducted in a single dose,four-way crossover design. Blood samples were taken periodically andassayed for oxycodone concentrations using gas chromatography with massdetection (G/MS).

From the data, the following pharmacokinetic parameters were calculatedas set forth in Table 22 below:

TABLE 22 AUC, Treatment n · hr/ml Cmax, n/ml Tmax, hr Example 13, fasted207 9.7 5.3 Example 13, fed 261 14.8 6.4 Example 11, fasted 244 12.9 6.0Oxycontin, fasted 249 20.8 3.2

From the above data, it can be concluded that both Examples 11 and 13,but particularly Example 13, are suitable for once daily administration.This is shown graphically in FIG. 12.

EXAMPLE 23 Bioavailablity of Example 14 Tablets

A bioabailability study of oxycodone controlled release tablets ofexample 14 was conducted in 25 normal volunteers. These tablets wereadministered either with or without food. The study was conducted in asingle dose, randomized crossover design. Blood samples were takenperiodically and assayed for oxycodone concentrations using gaschromatography with mass detection (GC/MS). The plasma oxycodoneconcentration versus time curves are shown in FIG. 13.

From the data, the following pharmacokinetic parameters were calculated.

TABLE 23 Treatment AUC, ng · hr/ml Cmax, ng/ml Tmax, hr Example 14,fasted 422 39.3 3.1 Example 14, fed 416 35.3 4.8

Surprisingly, it was found that the controlled release oxycodone HClpreparation, which dissolved preferentially in low pH, does not showsubstantial food effect. From the Cmax data, it can be seen that thereis no significant change in blood oxycodone levels when the drug wastaken with food than without food (35.3/39.3=0.09). From the AUC (areaunder the curve) data, it appears that the amount of drug absorbed withor without food is similar (416/422=0.986).

EXAMPLE 24 Bioavailablity of HH-MEM 8 mg Capsules

A bioavailablity study of hydromorphone capsules of Examples 17 and 18was conducted using a single dose, five-way crossover study in 12 normalmale volunteers. The subjects received either 8 mg of Dilaudid tablet(immediate release) or 8 mg of HH-MEM capsules. Dilaudid tablets wereadministered after an overnight fast. MEM capsules were administeredwith or without food. Blood samples were taken periodically and assayedfor hydromorphone concentrations using gas chromatography with massdetection (G/MS). From the data, the following pharmacokineticparameters were calculated.

TABLE 24 AUC, Treatment n · hr/ml Cmax, n/ml Tmax, hr Example 17, fasted19.00 0.72 6.8 Example 17, fed 20.10 0.75 2.4 Example 18, fasted 19.230.76 3.9 Example 18, fed 21.47 0.93 1.9 Dilaudid, fasted 14.55 3.69 0.7

From the data, both formulations 17 and 18 would be suitable foronce-a-day administration both not having a food effect, and in factExample 17 looks ideal. The data of Example 17 is shown graphically inFIG. 14 and the data of Example 18 is shown graphically in FIG. 15.

EXAMPLE 25 Steady State Bioavailablity of HH-MEM 8 mg Capsules

To assess steady state plasma levels and the effect of food onhydromorphone, a single dose, two-way crossover study was conducted in12 normal male volunteers. The subjects received either 4 mg of Dilaudid(immediate release) every 6 hours or 16 mg of the capsules according toExample 17 every 24 hours. Venous blood samples were taken atpredetermined time points. The plasma hydromorphone concentrations werequantitated using gas chromatography with mass detection (G/MS).

From the data from day 4, the following pharmacokinetic parameters werecalculated and are set forth in Table 25 below.

TABLE 25 AUC, Cmax, Treatment n · hr/ml n/ml Cmin, n/ml Tmax, hr Example17 36.08 2.15 1.49 5.8 Dilaudid 33.53 3.44 0.94 1.6

The results are shown graphically in FIG. 16. From this data it can beseen that Example 17 is an ideal product for once-a-day administrationfor either single dose or multiple dose administration.

EXAMPLE 26 Bioabailability of HH-MEM 8 mg Capsules

To assess bioavailablity and effect of food on hydromorphone MEMcapsules, a single dose, three-way crossover study was conducted in 12normal male volunteers. The subjects received either 8 mg of Dilaudidtablet (immediate release) or 8 mg of HH-MEM (Example 19) Dilaudidtablets were administered after an overnight fast. MEM capsules wereadministered with our without food. Venous blood samples were taken atpredetermined at time points. The plasma hydromorphone concentrationswere quantitated using gas chromatography with mass detection (G/MS).

From the data, the following pharmacokinetic parameters were calculatedand are set forth in Table 26 below.

TABLE 26 AUC, Cmax, Treatment n · hr/ml n/ml Tmax, hr Example 19, fasted15.83 0.52 5.6 Example 19, fed 16.55 0.65 4.1 Dilaudid, fasted 16.543.15 0.8

From the above data it can be concluded that a once-a-day Hydromorphoneproduct can be produced using other ingredients than are used forExamples 17 and 18. This data is shown graphically in FIG. 17.

EXAMPLE 27 Tramadol HCl 200 mg SR Tablet

The following formula is used to prepare melt extrusion granulation andtablet.

TABLE 27 Percentage Ingredients Amt (mg)/Tablet in Formula Tramadol HCl200 53.4 Eudragit RSPO 74 19.8 Tributyl Citrate 14.8 4.0 Stearyl Alcohol74 19.8 Talc 7.4 2.0 Magnesium Stearate 3.8 1.0 Total 374 100

Granulation Manufacture

a. Extruder system description—The twin screw extruder is consisted of apair of counterrotating screws and a barrel block equipped withheating/cooling zones. The stranded extrudate is congealed on a conveyorbelt and cut into pellets of the desirable size.

b. Manufacturing procedure-

1. Blend the drug and all the excipients in a proper mixer.

2. Place the mixture in a powder feeder.

3. Set temperatures of the extruder heating zones to approximately 65°C.

4. Set the extruder screw rotation speed to 40 rpm.

5. Start the feeder and the conveyor.

6. After the excipients are melted and the drug embedded in the moltenmixture, the viscous mass is extruded as spaghetti-like strands.

7. The extrudate is congealed and hardened while being carried away on aconveyor belt.

8. The stranded extrudate was cut into pellets of 2 mm in diameter and2-8 cm in length.

Tabletting

The pellets were milled into granules through a suitable screen. Thegranulation was blended with talc and magnesium stearate. The mixturewas then compressed into capsule-shaped tablets.

Dissolution Method

1. Apparatus—USP Type II (paddle), 100 rpm at 37° C.

2. The tablet was placed in a tablet sinker clip and immersed in eachvessel.

3. Media—900 ml pH 6.5 phosphate buffer.

4. Analytical method—High performance liquid chromatography.

The above tablets were founded to have the following dissolutionresults:

TABLE 27a Time (hr)  1  2  4  8 12 18 24 Mean % dissolved 24 33 45 61 7182 88

EXAMPLE 28 Tramadol HCl 200 mg SR Tablet

The following formula is used to prepare melt extrusion granulation andtablet with a slower dissolution profile than Example 27.

TABLE 28 Percentage Ingredients Amt (mg)/Tablet in Formula Tramadol HCl200 44.1 Ethyl cellulose 110 24.3 Tributyl Citrate 22 4.9 StearylAlcohol 110 14.3 Talc 7.4 1.6 Magnesium Stearate 3.4 0.8 Total 453.2 100

The manufacturing procedure and dissolution method are the same asdescribed in Example 27. Additional dissolution media used include pH1.2 simulated gastric fluid (SGF) without enzyme, pH 7.5 simulatedintestinal fluid (SIF) without enzyme, and pH 4 phosphate buffer.

The above tablets were found to have the following dissolution results:

TABLE 28a Time (hr) Mean % dissolved  1  2  4  8 12 18 24 SGF 18 26 3549 59 70 80 pH4 17 25 34 49 60 73 83 pH6.5 17 23 33 46 57 70 81 SIF 1723 32 45 56 68 78

The results show that the dissolution profiles of Tramadol SR tablets inmedia of different pH values are similar. Based on our experience withsimilar formula of other opiates, a formula which demonstrates pHindependent dissolution profile would provide a consistent drug releaseprofile in vivo without food effect.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

It is claimed:
 1. A sustained-release pharmaceutical formulationcomprising an extruded blend of a therapeutically active agent, one ormore hydrophobic materials selected from the group consisting ofalkylcelluloses, acrylic polymers, and mixtures thereof; and one or morehydrophobic fusible carriers having a melting point from about 30° toabout 200° C. and selected from the group consisting of natural orsynthetic waxes, fatty acids, fatty alcohols, and mixtures thereof, saidextruded blend divided into a unit dose containing an effective amountof said therapeutically active agent to render a desired therapeuticeffect and providing a sustained-release of said therapeutically activeagent for a time period of from about 8 to about 24 hours, said extrudedblend being formed by mixing the therapeutically active agent, the oneor more hydrophobic materials, and the one or more hydrophobic fusiblecarriers in an extruder to form said blend and extruding said blendthrough the extruder.
 2. The formulation of claim 1, wherein saidextrudate comprises a strand-shaped matrix cut into multi-particulateshaving a length of from about 0.1 to about 5 mm in length.
 3. Theformulation of claim 1, wherein said extrudate has a diameter of fromabout 0.1 to about 5 mm.
 4. The formulation of claim 1, wherein saidtherapeutically active agent is an opioid analgesic or apharmaceutically acceptable salt thereof.
 5. The formulation of claim 4,wherein said opioid analgesic is selected from the group consisting ofalfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, bupernorphine, butorphanol, clonitazene, codeine,cyclazocine, desomorphine, dextromoramide, dexocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl, butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, pharmaceuticallyacceptable salts thereof and mixtures thereof.
 6. The extrudate of claim5 wherein said opioid analgesic is selected from the group consisting ofmorphine, codeine, hydromorphone, hydrocodone, oxycodone, oxymorphone,dihydrocodeine, dihydromorphine, tramadol, pharmaceutically acceptablesalts thereof and mixtures thereof.
 7. The formulation of claim 2,wherein a unit dose comprising an effective amount of saidmultiparticulates to render a therapeutic effect is contained within agelatin capsule.
 8. The formulation of claim 2, wherein a unit dosecomprising an effective amount of said multiparticulates to render atherapeutic effect is compressed into a tablet.
 9. The formulation ofclaim 8, wherein said therapeutically active agent is tramadol or apharmaceutically acceptable salt thereof.
 10. The formulation of claim 7wherein said therapeutically active agent is an opioid analgesicselected from the group consisting of morphine, codeine, hydromorphone,hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine,tramadol, pharmaceutically acceptable salts thereof and mixturesthereof.
 11. The formulation of claim 10, which provides an in-vitrorelease (when assessed by the USP Paddle or Basket Method at 100 prm at900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 1 toabout 42.5% opioid released after one hour, from about 5 to about 65%opioid released after 2 hours, from about 15 to about 85% opioidreleased after 4 hours, from about 20 to about 90% opioid released after6 hours, from about 35 to about 95% opioid released after 12 hours, fromabout 45 to about 100% opioid released after 18 hours, and from about 55to about 100% opioid released after 24 hours, by weight.
 12. Theformulation of claim 10 which provides a peak plasma level at from about2 to about 8 hours after oral administration.
 13. The formulation ofclaim 10, which provides a W₅₀ from about 4 to about 12 hours.
 14. Theformulation of claim 10, which provides a rapid rate of initial rise inthe plasma concentration of the opioid after oral administration, suchthat the peak plasma level obtained in-vivo occurs from about 2 to about8 hours after oral administration.
 15. The formulation of claim 10,which provides a rapid rate of initial rise in the plasma concentrationof the opioid after oral administration, such that the absorptionhalf-life is from about 1 to about 8 hours after oral administration (inthe fasted state).
 16. The formulation of claim 10, which provides anin-vitro release (when assessed by the USP Paddle or Basket Method at100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. fromabout 12.5 to about 42.5% opioid released after one hour, from about 25to about 65% opioid released after 2 hours, from about 45 to about 85%opioid released after 4 hours, and greater than about 60% opioidreleased after 8 hours, by weight.
 17. A method of preparing asustained-release pharmaceutical extrudate suitable for oraladministration, comprising: blending in an extruder, a therapeuticallyactive agent together with (1) a hydrophobic material selected from thegroup consisting of alkylcelluloses, acrylic polymers, and mixturesthereof and (2) a hydrophobic fusible carrier selected from the groupconsisting of natural or synthetic waxes, fatty acids, fatty alcohols,and mixtures thereof, said retardant material having a melting pointbetween 30-200° C. and being included in an amount sufficient to furtherslow the release of the therapeutically active agent, heating said blendto a temperature sufficient to soften the mixture sufficiently toextrude the same; extruding said heated mixture as a strand having adiameter of from 0.1-3 mm; cooling said strand; and dividing said strandto form non-spheroidal multi-particulates of said extrudate having alength from 0.1-5 mm; and dividing said non-spheroidalmulti-particulates into unit doses containing an effective amount ofsaid therapeutically active agent, said unit dose providing asustained-release of said therapeutically active agent for a time periodof from about 8 to about 24 hours.
 18. The method of claim 17, whereinsaid therapeutically active agent is an opioid analgesic is selectedfrom the group consisting of alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, bupernorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dexocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, pharmaceuticallyacceptable salts thereof and mixtures thereof.
 19. The method of claim17, further comprising containing said unit dose of saidmultiparticulates within a gelatin capsule.
 20. The formulation of claim1, further comprising a plasticizer.
 21. The formulation of claim 1,further comprising a lubricant.
 22. The formulation of claim 20, whereinsaid plasticizer is selected from the group consisting of diethylphthalate, tributyl citrate, triacetin, and mixtures thereof.
 23. Theformulation of claim 21, wherein said lubricant is selected from thegroup consisting of magnesium stearate, stearic acid, talc, and mixturesthereof.
 24. The dosage form of claim 6, wherein said opioid analgesicis hydromorphone or a pharmaceutically acceptable salt thereof and theunit dose comprises from about 4 mg to about 64 mg of hydromorphone or apharmaceutically acceptable salt thereof.
 25. The dosage form of claim6, wherein said opioid analgesic is morphine or a pharmaceuticallyacceptable salt thereof and the unit dose comprises from about 5 mg toabout 800 mg of morphine or a pharmaceutically acceptable salt thereof.26. The dosage form of claim 6, wherein said opioid analgesic isoxycodone or a pharmaceutically acceptable salt thereof and the unitdose comprises from about 5 mg to about 400 mg of oxycodone or apharmaceutically acceptable salt thereof.
 27. The method of claim 18,further comprising blending a plasticizer with said therapeuticallyactive agent, said hydrophobic material, and said hydrophobic fusiblecarrier prior to heating said blend.
 28. The method of claim 32, whereinsaid plasticizer is selected from the group consisting of diethylphthalate, tributyl citrate, triacetin, and mixtures thereof.
 29. Themethod of claim 19, wherein said opioid analgesic is hydromorphone or apharmaceutically acceptable salt thereof and the unit dose comprisesfrom about 4 mg to about 64 mg of hydromorphone or a pharmaceuticallyacceptable salt thereof.
 30. The method of claim 19, wherein said opioidanalgesic is morphine or a pharmaceutically acceptable salt thereof andthe unit dose comprises from about 5 mg to about 800 mg of morphine or apharmaceutically acceptable salt thereof.
 31. The method of claim 19,wherein said opioid analgesic is oxycodone or a pharmaceuticallyacceptable salt thereof and the unit dose comprises from about 5 mg toabout 400 mg of oxycodone or a pharmaceutically acceptable salt thereof.32. The dosage from claim 6, wherein said opioid analgesic hydromorphoneor a pharmaceutically acceptable salt thereof and the unit dosecomprises from about 4 mg to about 64 mg of hydromorphone or apharmaceutically acceptable salt thereof.
 33. The dosage from claim 6,wherein said opioid analgesic is morphine or a pharmaceuticallyacceptable salt thereof and wherein said unit dose comprises from about5 mg to about 800 mg of morphine or a pharmaceutically acceptable saltthereof.
 34. The dosage form of claim 6, wherein said opioid analgesicis oxycodone or a pharmaceutically acceptable salt thereof and whereinsaid unit dose comprises from about 5 mg to about 400 mg of oxycodone ora pharmaceutically acceptable salt thereof.